This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Docosahexaenoic acid (DHA 22:6) is a long chain n-3 polyunsaturated fatty acid that is known to have anticancer properties. While the mechanisms of the growth inhibitory and cytotoxic effects of DHA on tumor cells are yet to be fully elucidated, the involvement of lipid peroxidation has been well recognized. There are well-evolved antioxidant enzyme systems in mammalian cells, which play an important role in attenuating oxidative stress caused by various intra- and extra- cellular stimuli. Among the primary antioxidant enzymes, superoxide dismutase 1 (SOD-1) functions in reducing cellular superoxides and has been suggested to be a potential molecular target for cancer therapy. We have recently demonstrated that DHA selectively reduces SOD-1 gene expression in cancer cells at mRNA and protein levels, thereby weakening cellular antioxidant forces and enhancing oxidative potential. Our preliminary studies further show that DHA lowers mRNA levels of SOD-1 by suppressing SOD-1 gene transcription. We therefore hypothesize that targeting SOD-1 is a novel cellular mechanism whereby DHA exerts its anticancer action. Two specific aims are proposed to test this hypothesis:1) To characterize the cellular mechanisms of DHA-induced suppression of SOD-1 gene transcription in human cancer cells. This effort will be primarily directed to identify DNA binding elements in the SOD-1 gene promoter that mediate DHA's suppressive effect and the signaling molecules and transcription factors involved. 2) To examine the role of SOD-1 in DHA-induced growth inhibition of cancer cells in nude mouse xenograft models. This will focus on determining the effects of altered SOD-1 gene expression on DHA-induced growth inhibition of cancer cells in vivo. The proposed studies are directly relevant to the prevention and treatment of human cancer and will contribute to our understanding of the cellular and molecular mechanisms underlying DHA's anticancer activity. It is anticipated that results derived from the proposed studies will provide a biological basis for the development of novel strategies for cancer prevention and/or treatment using DHA. At that time the PI will seek independent RO1 funding from NIH to continue this line of research.